Gamma-hydroxybutyrate compositions containing carbohydrate, lipid or amino acid carriers

ABSTRACT

The present invention provides compositions comprising at least one GHB moiety bonded to at least one physiologically compatible carrier molecule. The compositions can enhance the uptake of the drug, deliver effective therapeutic doses in a time-delayed fashion, or can target specific organs.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.11/183,482, filed on Jul. 18, 2005, which is a divisional of U.S.application Ser. No. 10/381,224, filed on Mar. 21, 2003, which is a U.S.National Stage filing under 35 U.S.C. 371 from International ApplicationNo. PCT/US01/29569, filed Sep. 21, 2001 and published in English as WO02/24715 A2 on Mar. 28, 2002, which claims priority from U.S.Provisional Application Ser. No. 60/234,720 filed on Sep. 22, 2000, thedisclosures of which applications and publication are incorporated byreference herein in their entirety.

BACKGROUND OF THE INVENTION

Gamma-hydroxybutyric acid or “gamma-hydroxybutyrate” (GHB) is anendogenous compound with hypnotic properties that is found in many humanbody tissues. GHB is present, for example, in the mammalian brain, thehuman nervous system and other tissues. The extraordinary range of thepharmacological effects of GHB or its salts has attracted scientificattention for more than three decades. For example, GHB has been foundto have tissue-protective effects in animals and man in many differentorgans including brain, liver, lung, heart, kidney, gut and pancreatic Bcells. In brain the highest GHB concentration is found in thehypothalamus and basal ganglia and GHB is postulated to function as aneurotransmitter (Snead and Morley, 1981). The neuropharmacologiceffects of GHB include increases in brain dopamine, depression ofglucose utilization but not oxygen consumption in the brain, andhypothermia. GHB is converted to succinate and then metabolized via theKrebs cycle. Clinical trials have shown that GHB increases delta sleepand improves the continuity of sleep (Ladinsky et al., 1983; Stock etal., 1973; Laborit, 1973; Lapierre et al., 1990; Yamada et al., 1967;Grove-White and Kelman, 1971; Scharf, 1985).

In healthy human volunteers, low doses (about 30 mg/kg) of GHBmonosodium salt (sodium oxybate) promote a normal sequence of NREM andREM sleep lasting about 2-3 hours. These low doses also can induce REMand slow wave sleep and, in contrast to the hypnotics in common use,without the development of tolerance to these sleep-inducing effects intime. In addition, GHB increases total sleep time and REM sleep, and itdecreases REM latency (Mamelak et al., 1973; Yamada et al., 1967; Bedardet al., 1989), reduces sleep apnea (Series et al., 1992; Scrima et al.,1987), and improves general anesthesia (Hasenbos and Gielen, 1985).

Studies by R. Broughton and M. Mamelak, Can. J. Neur. Sci., 7, 23(1980), L. Scrima et al., Sleep, 13, 479 (1990), and M. B. Scharf etal., Am. Fam. Phys., 143 (July 1988) have evaluated the effects of GHBin the treatment of narcolepsy. The results of these studies confirmthat GHB treatment substantially reduces the signs and symptoms ofnarcolepsy (e.g., daytime sleepiness, cataplexy, sleep paralysis andhypnagogic hallucinations).

GHB has several clinical applications other than the treatment of sleepdisorders. GHB has been reported to reduce alcohol craving, the numberof daily drinks consumed, and the symptoms of alcohol withdrawal inpatients (Gallimberti et al., 1989; Gallimberti et al., 1992; Gessa etal., 1992). GHB has been used to decrease the symptoms of opiatewithdrawal, including both heroin and methadone withdrawal (Gallimbertiet al., 1994; Gallimberti et al., 1993). It has analgesic effects thatmake it suitable as a pain reliever (U.S. Pat. No. 4,393,236).Intravenous administration of GHB has been reported to reduceintracranial pressure in patients (Strong, A. 1984). Also administrationof GHB was reported to increase growth hormone levels in patients (Gerraet al., 1994; Oyama et al., 1970). GHB is also an effective therapeuticagent for the treatment of chronic fatigue syndrome and fibromyalgia(Scharf, U.S. Pat. No. 5,990,162).

Unfortunately, the efficacy of GHB is limited by the high doses requiredto produce a therapeutic effect and by its short duration of action.Thus, a need exists for GHB compositions that can enhance the uptake ofthe drug, deliver effective therapeutic doses in a time-delayed fashion,and target specific organs.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula (I):

wherein Y is H or a hydroxyl-protecting group, X is the residue of acarbohydrate and n has a value of 1 to the number of available hydroxylgroups in said carbohydrate, or a pharmaceutically acceptable saltthereof.

Preferably, X is a saccharide, and Y is H, a (C₄-C₆)acetal, (C₁-C₅)acylor (C₁-C₅)alkyl.

Preferred carbohydrates are water-soluble or water-dispersible. In yetanother preferred embodiment of the invention, X is the residue of amonosaccharide, the residue of a disaccharide or the residue of apolysaccharide.

In such compounds, the monosaccharide, disaccharide or polysaccharidecan contain at least one CHOH—CHOH residue that is protected as anacetal or ketal.

Examples of compounds of formula (I) include1,2,3,4,6-pentakis(4-hydroxy-butyroyl)hexanose;6-(4-hydroxy-butyroyl)hexanose and1,2,3,4,6-pentakis(4-acetoxybutyroyl)hexanose.

In a further preferred embodiment of the compound of formula (I), X isthe residue of a chemically-modified cellulose. Usefulchemically-modified cellulose compositions include water-soluble orwater-dispersible celluloses such as hydroxypropyl-methylcellulose,hydroxypropylcellulose or hydroxyethylcellulose.

Further provided by the present invention is a compound of formula (II):

(R¹O(CH₂)₃CO₂)_(m)(ROC(O)(CH₂)₃OC(O))_(q)—(X)—(Y)_(n)-(Z)_(n)-(CO₂(CH₂)₃CO₂R)_(p)(O₂C(CH₂)₃OR′)_(k)  (II)

wherein R′ is H or a hydroxyl protecting group, R′ is H, (C₁-C₄)alkyl orbenzyl, X and Z are each residues of a hydroxy group-containing aminoacid or a bis(carboxy)amino acid, Y is a moiety covalently linking X andZ, n is 0-1, m and k are 0 to the number of available OH groups is X andZ, q and p are 0 to the number of available CO₂ groups on X and Z, withthe proviso that m and q are not both zero and p and k are not bothzero, or a pharmaceutically acceptable salt thereof.

An embodiment of the compound of formula II is a compound of formula(III):

wherein R¹ is H or a hydroxyl-protecting group, R is H, (C₁-C₄) alkyl orbenzyl, X is a residue of a hydroxy group-containing amino acids, Z is aresidue of a hydroxy group-containing amino acid or a bis(carboxy)aminoacid, Y is a moiety covalently linking X and Z, n is O-1, m is 1 to thenumber of hydroxy groups on amino acid X, p is 1 to the number of CO₂Hgroups on the amino acid X or Z, or a pharmaceutically acceptable saltthereof.

Preferably, m, p, q and k are individually 0-5, more preferably O-3, andmost preferably 0-2.

In one preferred embodiment of the compound of formula (III), m=p=1, nis O and X is glutamic acid, tyrosine, aspartic acid, threonine, or aserine. In another preferred embodiment of the compound of formula(III), m=p=1, n is 1, and Y is C(O)CH₂CH₂C(O), or C(O)CH═CH(CO).

The present invention also provides a compound of formula (IV):

wherein L and L′ are individually H, (C₁-C₆)alkyl or a hydroxylprotecting group or an organic moiety comprising at least one fattyalcohol, ester or analog thereof. At least one of L and L′ is saidmoiety (the FA moiety). Preferably, the FA moiety is (A)(Y)(Z)_(n), andwherein A is (C₂-C₆)alkyl, Y is H, OH, N(R¹)(R²)(R³) or [—O(PO₃⁻)-L-N(R¹)(R²)(R³)] wherein R¹, R² and R³ are each (C₁-C₄)alkyl or R¹and R² together with N are a (C₅-C₇)heterocyclic ring, optionallysubstituted with 1 or 2 N(R³), S, non-peroxide O or a combinationthereof; n is 1-2 and Z is YR, wherein Y is O, S, NH, N(CH₃), NHC(O) orOC(O) and R is (C₈-C₂₂)alkyl, optionally substituted with 1-2 doublebonds.

Preferably, one of L or L′ is (A)(Y)(Z)_(n) and the other is H; n=1, YZis (C₁₀-C₂₀)alkylC(O), R¹, R² and R³ are methyl and/or A is propyl orethyl. Preferably, when L′ is a 2-substituted lecithin moiety, i.e., theC²OC(O)R² moiety of lecithin is replaced by C²OC(O)(CH₂)₃OL and Y ishexadecanoyl; L is not H. Preferably n=1 and (A)(Y)(Z)_(n) is—CH[CH₂Y][CH₂Z], e.g., is derived by replacement of the 2′-acyloxylmoiety of lecithin with L-O(CH₂)₃C(O)—. When one of L or L′ is1,3-dihexdecanoylprop-2-yl, the other is not H.

Generally, L and L′ are derived from organic polyols, such as glycerol,ethylene glycol, propylene glycol, 2,2′-hydroxyethyl ether and the like.The organic moieties L and L′ can also be simple fatty acid esters ofC⁴—OH or fatty alcohol esters of CO₂H.

The present invention also provides compounds of formula (V):

wherein L is defined above, n is 2-6, preferably 2-5, most preferably2-3, and L″ is (C₂-C₁₂) alkyl, preferably (C₃-C₁₀)alkyl, most preferably(C₃-C₆)alkyl, wherein the alkyl chain is optionally interrupted by about1-3-O— moieties, i.e., is the residue of an alkylene polyol, preferablya 1,ω-alkylene diol such as 1,3-propane diol, or a polyoxyalkyleneglycol. Examples of compounds of formula (V) include1,2,3-tris(4-hydroxy-butyroyoxyl)propane and1,3-bis(4-acetoxybutyroyoxyl)propane.

The present invention also provides a pharmaceutical compositioncomprising an effective amount of the compound of formula (I), (II),(III) or (IV), or mixtures thereof in combination with apharmaceutically acceptable carrier. The pharmaceutical composition ofthe present invention may be adapted for parenteral, oral, topical orlocal administration.

The present invention also provides a therapeutic method comprisingadministering to a mammal afflicted with a pathology or conditionameliorated by GHB, an amount of a compound of formula I, II, III, IVand/or V effective to treat said pathology or condition.

As used herein, the term “effective amount” means that the compositioncan deliver an amount of GHB to a target cell, tissue or organ effectiveto accomplish a therapeutic objective, i.e., to alter cellularmetabolism or energetics or to ameliorate at least one symptom of one ofthe pathologies discussed herein.

BRIEF DESCRIPTION OF THE FIGURES

The following drawings from part of the present specification and areincluded to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein.

FIG. 1A shows a compound comprising the GHB pentaester of a fullycharged hexopyranose.

FIG. 1B shows GHB triesters of partially charged hexopyranoses.

FIG. 2 shows a GHB-sucrose ester.

FIG. 3 shows a GHB linked to representative amino acids.

FIG. 4 shows a GHB linked to amino acid conjugates.

DETAILED DESCRIPTION OF THE INVENTION A. Definitions

The term “amino acid” comprises the residues of the natural amino acids(e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, Leu,Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D or L form, as wellas unnatural amino acids (e.g. phosphoserine, phosphothreonine,phosphotyrosine, hydroxyproline, gamma-carboxyglutamate; hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,ornithine, citruline, α-methyl-alanine, para-benzoylphenylalanine,phenylglycine, propargylglycine, sarcosine, and tert-butylglycine). Theterm also comprises natural and unnatural amino acids bearing aconventional amino protecting group (e.g. acetyl or benzyloxycarbonyl),as well as natural and unnatural amino acids protected at the carboxyterminus (e.g. as a (C₁-C₆)alkyl, phenyl or benzyl ester or amide; or asan α-methylbenzyl amide). Other suitable amino and carboxy protectinggroups are known to those skilled in the art (See for example, T. W.Greene, Protecting Groups In Organic Synthesis; Wiley: New York, 1981,and references cited therein). An amino acid can be linked to theremainder of a compound of formula I through the carboxy terminus, theamino terminus, or through any other convenient point of attachment,such as, for example, through the sulfur of cysteine.

The term “hydroxy amino acid” includes naturally occurring, syntheticand semi-synthetic amino acids, such as serine, threonine, tyrosine andhydroxyproline.

Preferably the amino acids are α-amino acids, most preferably withω-hydroxyl groups.

The term “carbohydrate” as used herein is defined to include polyhydroxyaldehydes, or polyhydroxy ketones or substances that yield suchcompounds on hydrolysis. The term “carbohydrate” includesmonosaccharides, oligosaccharides, disaccharides, trisaccharides,tetrasaccharides, pentasaccharides, hexasaccharides, polysaccharides,homopolysaccharides, and heteropolysaccharides. The term includes any ofthe aldoses, as well as glucose, dextrose, mannose, galactose arabinose,xylose, ribose, fructose, sucrose, altrose, allose, idose, gulose,talose, lyxose, threose, erythrose, apiose, and any of the same in acidform. The term also includes deoxy sugars and deoxy-aldoses, includingrhamnose and fucose. The term further includes glyceraldehyde,cellulose, starch, glycogen, and amylose. The term also includescarbohydrate derivatives, such as acetals, ketals, acyl esters and thelike. Chemically modified polysaccharides such as sucralfate andmodified starches are also within the scope of the term. Additionalsuitable carbohydrates of the present invention may be found in Noller,C., Chemistry of Organic Compounds, 2nd ed. (W. B. Saunders Co., 1957).

The term “saccharide” includes monosaccharides, disaccharides,trisaccharides and polysaccharides. The term includes glucose, sucrose,fructose and ribose, as well as deoxy sugars such as deoxyribose and thelike. Saccharide derivatives can conveniently be prepared as describedin International Patent Applications Publication Numbers WO 96/34005 and97/03995.

The term “oligopeptide” describes a sequence of 2 to 25 amino acids(e.g. as defined hereinabove) or peptidyl residues. The sequence may belinear, branched or cyclic. For example, a cyclic peptide can beprepared or may result from the formation of disulfide bridges betweentwo cysteine residues in a sequence. An oligopeptide can be linked tothe remainder of a compound of formula I through the carboxy terminus,the amino terminus, or through any other convenient point of attachment,such as, for example, through the sulfur of a cysteine. Preferably apeptide comprises 3 to 25, or 5 to 21 amino acids. Peptide derivativescan be prepared as disclosed in U.S. Pat. Nos. 4,612,302; 4,853,371; and4,684,620.

The term “linking moiety” or “linker” as used herein refers to an atleast divalent organic molecule that can join two amino acids oroligopeptidyl residues by reaction with functional groups therein. Suchmoieties include alkane and alkene dicarboxylic acids and diamines.

The term “alkyl” includes branched, straight-chain and cyclic alkylgroups, including (cycloalkyl)alkyl.

A fatty alcohol is a (C₈-C₂₂)alkanol, preferably a (C₁₀-C₂₀)alkanol,optionally comprising 1-3 double bonds; a fatty acid is a(C₈-C₂₂)alkanoic acid (i.e., (C₁-C₁₁)C(O)OH), optionally comprising 1-3double bonds.

The term “hydroxyl protecting group” includes removable hydroxy moietyprotecting groups known to the art, such as acid- or base-labile groupssuch as acetals (THP, (1-ethoxy)ethyl), tris(alkyl)silyl groups (Me₃,Si, (t-Bu(Me₂)Si)), (C₂-C₇)acyl groups (acetyl), as well as groups thatcan be removed by hydrogenolysis, such as benzyl. See, also, part(C)(a), hereinbelow, which references additional OH protecting groups.

B. Applications

GHB has been shown to be effective in treating narcolepsy and sleepdisorders (Lee, 1977; Mamelak, 1977; Hoes, 1980; Scharf, 1985; Scrima,1990; Gallimberti, 1992; Series, 1992; Lammers, 1993), reducing alcoholcraving and alcohol withdrawal symptoms (Gallimberti et al., 1989;Gallimberti et al., 1992; Gessa et al., 1992), reducing opiatewithdrawal symptoms (Gallimberti et al., 1994; Gallimberti et al.,1993), reducing pain (U.S. Pat. No. 4,393,236), reducing intracranialpressure in patients (Strong, A., 1984), and increasing growth hormonelevels in patients (Gerra et al., 1994; Oyama et al., 1970). Thecompounds and compositions of the present invention can also be used inthe treatment of any of these disorders or conditions in patients.

GHB has been used with other analgesics, neuroleptics, or with asubliminal barbiturate dose for use as an anesthesia. GHB has been usedin closed cranio-cerebral trauma and as soporifics (U.S. Pat. No.5,380,937). Therefore, the compounds of the present invention can alsobe used in combination with analgesics, neuroleptics or barbiturates foruse as an anesthesia. The inventors contemplate the use of the GHBcompositions of the present invention as a narcotic, hypnotic, or as asoporific.

The present invention provides compounds and pharmaceutical compositionsthat can be used in the treatments of hypnosis; narcolepsy (particularlycataplexy); drug abuse; anxiety; cerebrovascular diseases; centralnervous system disorders, neurological disorders, including Parkinson'sDisease and Alzheimer Disease; Multiple Sclerosis; autism; depression;inflammatory disorders, including those of the bowel, such as irritablebowel disorder, regional illitis, and ulcerative collitis; autoimmuneinflammatory disorders; certain endocrine disturbances and diabetes. Thepresent compounds can also be administered for the purpose of tissueprotection, including protection following hypoxia/anoxia such as instroke, organ transplantation, organ preservation, myocardial infarctionor ischemia/reperfusion injury; protection following radiation,progeria, or an increased level of intracranial pressure, e.g., due tohead trauma. The present compounds can be used to treat otherpathologies believed to be caused or exacerbated by lipid peroxidationand/or free radicals, such as pathologies associated with oxidativestress, including normal aging.

C. Availability and Preparation of Compounds of the Present Invention

GHB is available from the Aldrich Chemical Co., Milwaukee, Wis., and canbe employed to prepare the compounds within the scope of formula (I) or(II). The GHB compositions of the present invention can be prepared byand administered by any of the means described herein, particularlythose described in the section and the examples, or by any means aswould be known to those of skill in the art.

A compound of the present invention can be employed as the free acid oralcohol, or as a pharmaceutically acceptable salt or ester thereof. Suchsalts can be formed from acids or amino groups described herein, bymethods available to one or ordinary skill in the art. In cases wherecompounds are sufficiently basic or acidic to form stable salts withnontoxic organic acids or metal salts, administration of the compoundsas salts may be appropriate. Examples of pharmaceutically acceptablesalts are organic acid addition salts formed with acids which can form aphysiological acceptable anion, for example, tosylate, methanesulfonate,acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and αglycerophosphate. Suitable inorganic salts mayalso be formed, including hydrochloride, sulfate, nitrate, bicarbonate,and carbonate salts. Pharmaceutically acceptable salts may be obtainedusing standard procedures well known in the art, for example by reactinga sufficiently basic compound such as an amine with a suitable acidaffording a physiologically acceptable anion. Alkali metal (for example,sodium, potassium or lithium) or alkaline earth metal (for examplecalcium) salts of carboxylic acids can also be made. The cations canalso be readily exchanged with other metal or organic cations, such asCa⁺, K⁺, Li⁺, or (R)₄N⁺ wherein each R is H, phenyl, (C₁-C₆)alkyl orhydroxy(C₁-C₆)alkyl, i.e., ammonium or hydroxyethyl amine salts.

Hydroxy protecting groups such as esters, ethers, acetals and ketals maybe utilized in the present compounds. Useful hydroxy protecting groupsare described in Greene, T. W.; Wutz, P. G. M., “Protecting Groups inOrganic Synthesis”, 2nd ed., John Wiley & Sons, Inc (1991).

a) Preparation of Carbohydrate-GHB Compounds

GHB can be esterified with (C₁-C₄)alkanols or the benzyl ester prepared.For ester preparation methods, see S. Ege, Organic Chemistry, p.454-455, 459, 466-467 (D.C. Heath and Co., 1984). See also, Pouillart etal., Eur. J. Pharm. Sci., 7, 93-106 (1998). Then the OH group can beprotected by formation of an acetal or by alkanoylation or benzoylationwith an alkanoyl or benzoyl chloride or with anhydrides. Other usefulacid- and base-labile hydroxy-protecting groups are described in Greene,T. W.; Wutz, P. G. M. “Protecting Groups In Organic Synthesis” secondedition, 1991, New York, John Wiley & Sons, Inc.

The ester can be removed and the acid can be activated if necessary,i.e., by formation of an acid chloride or anhydride. For preparationmethods for 4-hydroxy-butanoic acid and its derivatives, see, Marvel etal., J. Am. Chem. Soc., 51, 260 (1929); Japanese patent 63174947, GermanPat. Nos. 237310, 237308 and 237309.

The activated carboxyl group of GHB can be reacted with the targethydroxyl groups in various sugars via ester bonds, as described, forexample, in P. Pouillart et al., Eur. J. Pharm. Sci., 7, 93 (1998), P.R. Pouillart, Life Sciences, 63, 1739 (1998); P. Pouillart et al., J.Pharm. Sci., 81, 241 (1992), and references cited therein. Most types ofsugars, including triose (or glycerol) tetroses, pentoses and hexosescan be used to make the compounds of the present invention. In thelatter two cases, the open chain and ring (pyranoses and furanoses)forms may be used as scaffolds. An example of hexopyranose is depictedin FIG. 1 a, where a maximum of 5 GHB molecules can be anchored to eachsugar monomer.

The therapeutic potential of these compounds is dependant on thestability of the compounds in various environments. It is contemplatedthat fully charged GHB compounds can be synthesized from sucrose(containing a furanose and a pyranose ring), glucose and one from anyopen chain hexose. These compounds may be synthesized by a single stepfrom free GHB or from its lactone.

In a fully charged molecule, i.e, (GHB)₅-Sugar, the hydrocarbon chainsmay provide adequate protection from enzymes present in the digestivetract. These compositions may be susceptible to acid catalyzedhydrolysis, which depends on the steric environments around each esterbond. For example, the 6-OH ester bond will be readily hydrolyzed. Thesemolecules may be viewed as miniature micelles and can be transportedinto the circulatory system via the fat absorption mechanism.

Linking GHB to partially charged sugars may provide for better uptakeand delivery of the drug. As seen in FIG. 1 b, the depicted compound hasonly 3-GHBs attached to the sugar. The choice of hydroxyl groups foresterification can be based on the rates of hydrolysis of thecorresponding esters so that desired levels of free GHB can bemaintained within the cells of the target organ.

Free hydroxyl groups can be used to anchor various groups. Stericshielding of GHB-ester linkages enhances the stability of the compoundsin acidic medium. For example, one or more pairs of adjacent OH groupgroups on the sugar ring can be protected as acetals or as ketals, astaught by Pouillart et al., cited above, using acetals. The ketone canbe varied in bulk, in order to shield the ester linkages to a greater orlesser extent. The attachment of lipophilic groups, such as steroids orfatty acids, to GHB via e.g., ketal or acetal linkages, can enhance thetransfer across the blood-brain barrier. The use of a ketosteroid orbenzaldehyde to form a ketal or acetal is shown in FIG. 1( b). Alipophilic composition may also be useful for delivery of GHB via salvesor dermal patches. Free hydroxyl groups of the sugar may also be used toattach a second complementary therapeutic agent to the GHB composition.

b) Preparation of GHB Amino Acid Compounds

Amino acids (AA), serine, threonine, tyrosine, aspartic acid andglutamic acid contain side chains containing OH groups and/or secondCO₂H groups that can be coupled to GHB by ester linkages, followingN-protection (See FIG. 3). Each of these compounds could be linked totwo GHB molecules. Alternatively, the carboxylic acid of GHB can bereacted with an acid-protected amino acid to form the amide from theamine of the amino acid. Because the ester linkages of these compoundshave different steric environments, the hydrolysis rates of thesecompounds in vivo will vary. A significantly slow rate of hydrolysiswill be seen with serine and threonine, due to the ester linkagesassociated with their side chains. For tyrosine, the ester linkageassociated with the phenoxy side chain can be very rapidly hydrolyzed.Single amino acid compounds, i.e., AA-(GHB)₂ can only deliver 2 GHBmolecules, and due to the lack of steric shielding, these compounds mayhave limited stability in the stomach pH. However, tailored smallpeptides having 3 to 5 amino acids can significantly improve thequantity of GHB delivered and have enhanced stability.

It is contemplated that the compounds of the present invention maycomprise two or more amino acids. Such compounds can be constructed byusing covalent linking moieties such as succinic acid to couple theamino acids tyrosine and threonine, or using maleic acid to coupleaspartic and glutamic acids. Each of these conjugates comprises 4 GHBper molecule, where each ester linkage is in a significantly differentsteric shielding. (See FIG. 4). As backbones of the compounds, thesuccinic and maleic acid linkers have significantly different degrees offlexibility. Succinic acid has full rotational freedom, whereas usingmaleic acid, GHB molecules will be held in a cis orientation. Eachcompound, having two amide and four ester linkages, can give rise todistinct structural organizations with different stability and cellularuptake.

c) Preparation of Compounds of Formulas (IV) and (V)

Analogs of naturally occurring phospholipids and lipids are known to theart.

The compounds of formula III can be prepared as disclosed in PCT WO92/03462; U.S. Pat. No. 5,223,263; PCT/US91/04289; or PCT/US94/05855.Lecithin or a sphingolipid can be partially hydrolyzed to yield one ormore free OH groups and GHB attached as discussed above.

Compounds of formula (V) can be prepared by the reaction of polyols(L″(OH)_(n)) with 4-halobutyroylchloride, which is then hydrolyzed andthe 4-hydroxyl group protected, or the 4-halo group is displaced by L″O⁻or an equivalent thereof.

D. Administration

The invention provides a pharmaceutical formulation comprising acompound of formula (I), (II), or (III), together with one or morepharmaceutically acceptable carriers therefor and, optionally, othertherapeutic and/or prophylactic ingredients. The cations and carrier(s)must be “acceptable” in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof, i.e., they do not produce an adverse, allergic, or otheruntoward reaction when administered to an animal, or a human, atappropriate levels.

Pharmaceutical formulations include those suitable for oral orparenteral (including intramuscular, subcutaneous and intravenous)administration. Forms suitable for parenteral administration alsoinclude forms suitable for administration by inhalation or insufflationor for nasal, or topical (including buccal, rectal, vaginal, transdermalor sublingual) administration. The formulations may, where appropriate,be conveniently presented in discrete unit dosage forms, by bringing theactive compound into association with liquid carriers, solid matrices,semi-solid carriers, finely divided solid carriers or combinationsthereof, and then, if necessary, shaping the product into the desireddelivery system.

a) Parenteral Administration and Dosage Forms

The active compounds of the invention may be formulated for parenteraladministration, e.g., formulated for injection via intravenous,intraarterial, intramuscular, subcutaneous, intralesional,intraperitoneal or other parenteral routes. The preparation of anaqueous composition that contains a GHB agent as an active component oringredient will be known to those of skill in the art in light of thepresent disclosure.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions. The compounds of the invention may be lyophilized formore ready formulation into a desired vehicle where appropriate. Forinjection or infusion, the active agent can optionally be encapsulatedin liposomes. In all cases, the ultimate dosage form should be sterile,fluid and stable under the conditions of manufacture and storage.

The liquid carrier or vehicle can be a solvent or liquid dispersionmedium comprising, for example, water, ethanol, glycerol, a polyol (forexample, glycerol, propylene glycol, liquid polyethylene glycols, andthe like), vegetable oils, nontoxic glyceryl esters, and suitablemixtures thereof. The proper fluidity can be maintained, for example, bythe formation of liposomes, by the maintenance of the required particlesize in the case of dispersions, by the use of surfactants, or by theuse of a substance, such as lecithin (e.g., a coating). Solutions of theactive compounds as free acid or pharmacologically acceptable salts canbe prepared in water suitably mixed with hydroxypropylcellulose and/or apharmaceutically acceptable surfactant. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompounds in the required amount in the appropriate solvent with variousof the other ingredients as required, followed by filteredsterilization. Generally, dispersions are prepared by incorporating thevarious sterilized active ingredients into a sterile vehicle whichcontains the basic dispersion medium and the required other ingredientsfrom those enumerated above. In the case of sterile powders for thepreparation of sterile injectable solutions, the preferred methods ofpreparation are vacuum-drying and freeze-drying techniques which yield apowder of the active ingredient plus any additional desired ingredientfrom a previously sterile-filtered, pyrogen-free solution thereof. Thepreparation of more, or highly, concentrated solutions for directinjection is contemplated, where the use of DMSO as solvent (althoughDMSO may not now be a permitted human drug) is envisioned to result inextremely rapid penetration, delivering high concentrations of theactive agents to a small area.

The compounds according to the invention may be presented in unit doseform in ampules, pre-filled syringes, small volume infusion containers,multi-dose containers with an added preservative, or indwelling pumps ordispensers, or in devices which allow for sustained release of thecompounds.

The active GHB agent may be included within a therapeutic composition tocomprise about 0.1 to about 100 grams GHB per unit dosage form, andmultiple doses can also be administered. As an example, one dosage couldbe dissolved in 1 ml of isotonic NaCl solution and either added to 1000ml of fluid or injected at the proposed site of infusion (see, forexample, “Remington's Pharmaceutical Sciences” 15th Edition, pages1035-1038 and 1570-1580). Some variation in dosage will necessarilyoccur depending on the condition of the subject being treated. Theperson responsible for administration will, in any event, determine theappropriate dose for the individual subject.

b) Oral and Topical Administration and Dosage Forms

In addition to the compounds formulated for parenteral administration,other pharmaceutically acceptable forms include, e.g., tablets or othersolids; liposomal formulations; time release capsules; and any otherform currently used, including creams or lotions, which then may beadmixed with an aqueous medium for oral administration.

Pharmaceutical formulations suitable for oral administration may bepresented as discrete unit dosage forms such as hard or soft gelatincapsules, cachets or tablets each containing a predetermined amount ofthe active ingredient; as a powder or as granules; as a solution, asuspension or as an emulsion; or in a chewable base such as a syntheticresin or chicle for ingestion of the active ingredient from a chewinggum. The active ingredient may also be presented as a bolus, syrup,electuary or paste. Tablets and capsules for oral administration maycontain conventional excipients such as binding agents, fillers,lubricants, disintegrants, or wetting agents. The tablets may be coatedaccording to methods well known in the art, i.e., with enteric coatings.

The tablets, troches, pills, capsules and the like may also contain thefollowing: a binder, natural as gum tragacanth, acacia, cornstarch, orgelatin or synthetic as polyvinyl acetate; excipients, such as dicalciumphosphate; a disintegrating agent, such as corn starch, potato starch,alginic acid and the like; a lubricant, such as magnesium stearate; anda sweetening agent, such as sucrose, lactose, aspartame or saccharin maybe added or a natural or synthetic flavoring agent.

When the dosage unit form is a capsule for admixing with a specificvolume of an aqueous medium, it may contain, in addition to materials ofthe above type, a liquid carrier, such as vegetable oil or apolyethylene glycol. Various other materials may be present as coatingsor to otherwise modify the physical form of the dosage unit. Forinstance, tablets, pills, or capsules may be coated with gelatin, wax,shellac, sugar, natural or synthetic polymers, or both. A syrup orelixir may contain the active compounds, sucrose or fructose as asweetening agent, a preservative, a dye and/or a flavoring. Of course,any material used in preparing any unit dosage form should bepharmaceutically acceptable and substantially non-toxic in the amountsemployed.

Such compositions and preparations should contain at least 0.1% of theactive compound. The percentage of the compositions and preparationsmay, of course, be varied and may conveniently be between about 2 toabout 75% of the weight of the unit, or preferably between 25-60%. Theamount of active compounds in such therapeutically useful compositionsis such that a suitable dosage will be obtained.

The GHB-containing agent may be packaged separately from or incombination with the excipients, salts, flavorings or any othercomponents described herein, to be admixed with an aqueous medium in thecase of oral or injectable formulations, or they may be incorporateddirectly with the food (i.e., a beverage, candy bar or cake) of thediet.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid. Examples of useful dermatologicalcompositions which can be used to deliver the compounds of formula I,II, or III to the skin are known to the art; for example, see Jacquet etal. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith etal. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).

Useful solid carriers for dermatological compositions include finelydivided solids such as talc, clay, microcrystalline cellulose, silica,alumina and the like. Useful liquid carriers include water, alcohols orglycols or water-alcohol/glycol blends, in which the present compoundscan be dissolved or dispersed at effective levels, optionally with theaid of non-toxic surfactants. Adjuvants such as fragrances andadditional antimicrobial agents can be added to optimize the propertiesfor a given use. The resultant liquid compositions can be applied fromabsorbent pads, used to impregnate bandages and other dressings, orsprayed onto the affected area using pump-type or aerosol sprayers.

Ointments, pastes, gels, lotions, soaps and creams may, for example, beformulated with an aqueous or oily base with the addition of suitablethickening and/or gelling agents. Lotions may be formulated with anaqueous or oily base and will in general also contain one or moreemulsifying agents, stabilizing agents, dispersing agents, suspendingagents, thickening agents, or coloring agents. Thickeners such assynthetic polymers, fatty acids, fatty acid salts and esters, fattyalcohols, modified celluloses or modified mineral materials can beemployed.

For systemic administration or as topical administration to theepidermis, compound(s) of formula (I), formula (II), or formula (III)may be formulated as the active ingredient of a transdermal patch.Suitable transdermal delivery systems are disclosed, for example, in A.Fisher et al. (U.S. Pat. No. 4,788,603), Chien et al. (U.S. Pat. No.5,145,682) or R. Bawa et al. (U.S. Pat. Nos. 4,931,279, 4,668,506 and4,713,224). The active ingredient can also be delivered viaiontophoresis, e.g., as disclosed in U.S. Pat. No. 4,140,122, 4,383,529,or 4,051,842.

Formulations suitable for topical administration in the mouth includeunit dosage forms such as lozenges comprising active ingredient in aflavored base, usually sucrose and acadia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; mucoadherent gels, and mouthwashescomprising the active ingredient in a suitable liquid carrier.

When desired, the above-described formulations can be adapted to providesustained release of the active ingredient employed, e.g., bycombination with certain hydrophilic polymer matrices, e.g., comprisingnatural gels, synthetic polymer gels or mixtures thereof.

Pharmaceutical formulations suitable for rectal administration whereinthe carrier is a solid are most preferably presented as unit dosesuppositories. Suitable carriers include cocoa butter and othermaterials commonly used in the art, and the suppositories may beconveniently formed by admixture of the active compound with thesoftened or melted carrier(s) followed by chilling and shaping in molds.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing, inaddition to the active ingredient, such carriers as are known in the artto be appropriate.

For administration by inhalation, the compounds according to theinvention are conveniently delivered form an insufflator, nebulizer or apressurized pack or other convenient means of delivering an aerosolspray. Pressurized packs may comprise a suitable propellant such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount.

Alternatively, for administration by inhalation or insufflation, thecompounds according to the invention may take the form of a dry powdercomposition, for example, a powder mix of the compound and a suitablepowder base such as lactose or starch. The powder composition may bepresented in unit dosage form in, for example, capsules or cartridgesor, e.g., gelatin or blister packs from which the powder may beadministered with the aid of an inhalator or insufflator.

For intra-nasal administration, the compounds of the invention may beadministered via a liquid spray, such as via a plastic bottle atomizer.Typical of these are the Mistometer® (Wintrop) and the Medihaler®(Riker). Nasal solutions are usually aqueous solutions designed to beadministered to the nasal passages in drops or sprays. Nasal solutionsare prepared so that they are similar in many respects to nasalsecretions, so that normal ciliary action is maintained. Thus, theaqueous nasal solutions usually are isotonic and lightly buffered tomaintain a pH of 5.5 to 6.5, though other pH ranges disclosed herein thespecific example, such as pH 3 to about pH 9, or pH 6 to about 7.5, arecontemplated. In addition, preservatives, similar to those used inophthalmic preparations, and appropriate drug stabilizers, if required,may be included in the formulation. Various commercial nasalpreparations are known and include, for example, antibiotics andantihistamines and are used for asthma prophylaxis.

c) Dosages

A good safety profile for GHB consumption, when used long term fortreatment of narcolepsy, has been reported. Patients have been safelytreated for many years with GHB without development of tolerance(Scharf, 1985). Clinical laboratory tests carried out periodically onmany patients have not indicated organ or other toxicities (Lammers,1993; Scrima, 1990; Scharf, 1985; Mamelak, 1977; Mamelak; 1979;Gallimberti, 1989; Gallimberti, 1992; Gessa, 1992).

In the healthy volunteers study, the pharmacokinetics of three risingGHB doses (12.5, 25, and 50 mg/kg) were investigated. These findingsindicate that both the oral absorption and elimination processes of GHBwere capacity-limited though the degree of dose dependency was moderate(Palatini et al., 1993).

GHB has typically been administered in clinical trials as an oralsolution (Lee, 1977; Mamelak, 1977; Hoes, 1980; Scharf, 1985; Scrima,1990; Gallimberti, 1992; Series, 1992; Lammers, 1993). When used as anoral solution, the dosages have ranged from 20-45 milligrams perkilogram body weight, twice daily. (Mamelak, 1977.)

It will be appreciated that the amount of the compound of formula (I),(II), (III), (IV) or (V) required for use in treatment will vary notonly with the particular compound selected but also with the route ofadministration, the severity of the condition being treated and the ageand condition of the patient and will be ultimately at the discretion ofthe attendant physician or clinician.

Useful dosages of the compounds of formula (I), (II), (III), (IV) or (V)can be determined by comparing their in vitro activity, and in vivoactivity in animal models. Methods for the extrapolation of effectivedosages in mice, and other animals, to humans are known to the art; forexample, see U.S. Pat. No. 4,938,949.

Generally, the concentration of the compound(s) of formula (I), (II),(III), (IV) or (V) in a liquid composition, such as a lotion, will befrom about 0.01-25 wt-%, preferably from about 0.5-10 wt-%. Theconcentration in a semi-solid or solid composition such as a gel or apowder will be about 0.01-15 wt-%, preferably about 0.5-2.5 wt-%.

In general, however, a suitable dose will be in the range of from about0.05 to 50 gm per day; or preferably from about 0.05 to about 500 mg perkilogram body weight of the recipient per day, preferably in the rangeof 0.1 to 200 mg/kg/day.

The compound is conveniently administered in unit dosage form; forexample, containing 0.1-20 g, conveniently 1-7.5 g, or moreconveniently, 2-5 g of active ingredient per unit dosage form.

The total daily dose, i.e., of about 0.05-50 g, may be administered forabout 1-4 months, or longer, as needed.

Ideally, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.5 to about75 μM, preferably, about 1 to 50 μM, most preferably, about 2 to about30 μM. This may be achieved, for example, by the intravenous injectionof a 0.05 to 5% solution of the active ingredient, optionally in saline,or orally administered as a bolus containing about 1-100 mg of theactive ingredient. Desirable blood levels may be maintained bycontinuous infusion to provide about 0.01-5.0 mg/kg/hr or byintermittent infusions containing about 0.4-15 mg/kg of the activeingredient(s).

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

Example 1 Preparation of 1,3-Bis(4-bromobutyroyl)propane (VII)

A 500 ml round-bottomed flask was charged with 19.4 ml of pyridine in150 ml of dichloromethane (CH₂Cl₂), and stirring initiated as thesolution was cooled to 0° C. Propane-1,3-diol (8.0 g) was added, andstirring continued. A mixture of 26.4 ml of 4-bromobutyroyl chloride in75 ml CH₂Cl₂ was added dropwise to the stirred pyridine/CH₂Cl₂ andstirring continued for 5 hrs at 0° C. The reaction mixture was washedwith 300 ml H₂O, the organic layer was isolated and washed with 100 mlin HCl aq, 100 ml NaCl aq and dried over MgSO₄ (anhydrous). The solventswere removed in vacuo to yield the product (VII) as a translucent lowviscosity oil.

Example 2 Preparation of 1,3-Bis(4-acetoxybutyroyl)propane (VIII)

A solution of 20.6 g potassium acetate and 3.49 g potassium iodide in306 ml acetic anhydride was stirred and the product (VII) of Ex. 1added. The reaction mixture was refluxed with stirring for 12-16 hrs,then cooled to 25° C. and diluted with 100 ml EtOAc. The reactionmixture was filtered, and the filtrate concentrated in vacuo. Ethylacetate (400 ml) was added and the resultant solution was washed with2×200 ml of 50% aq. NaHCl₃. The organic layer was isolated, dried (MgSO₄an.), filtered and concentrated in vacuo. Purification by flashchromatography yielded product (VIII) in 66.3% yield as a viscous lightyellow oil (93% pure).

REFERENCES

-   Bedard et al., Clin. Neuropharmacol., 12(1) 29 (1989)-   Broughton and Mamelak, Can. J. Neur. Sci., 7, 23 (1980)-   Gallimberti et al., Lancet, 2(8666), 787 (1989)-   Gallimberti et al., Alcohol Clin. Exp. Res., 16(4) 673 (1992)-   Gallimberti et al., Neuropsychopharmacology, 9(1) 77 (1993)-   Gallimberti et al., Eur. Arch. Psychiatry Clin. Neurosci., 244(3)    113 (1994)-   Gerra et al., Int. Clin. Psychopharmacol., 9(3) 211 (1994)-   Gessa et al., Clin. Neuropharmacol., 15 Suppl. 1 Pt. A 303A (1992)-   Grove-White and Kelman, Br. J. Anaesth, 43(2) 110 (1971)-   Hasenbos and Gielen, Anaesthesia, 40(10) 977 (1985)-   Hoes et al., Encephale, 6(1) 93 (1980)-   Laborit, Laboratoire d'Eutonologie, Hopital Boucicaut Paris 15    France, 1973-   Ladinsky et al., Naunyn Schmiedebergs Arch Pharmacol., 322(1) 42    (1983)-   Lammers et al., Sleep, 16(3) 216 (1993)-   Lapierre et al., Sleep, 13(1) 24 (1990)-   Lee, Biochem Med., 17(3) 284 (1977)-   Mamelak et al., Lancet, 2(7824) 328 (1973)-   Mamelak et al., Biol. Psychiatry, 12(2) 273 (1977)-   Mamelak et al., Biol. Psychiatry, 14(5) 821 (1979)-   Oyama et al., Br. J. Anaesth., 42(12) 1105 (1970)-   Palatini et al., Eur. J. Clin. Pharmacol., 45(4) 353 (1993)-   Scharf et al., J. Clin. Psychiatry, 46(6) 222 (1985)-   Scharf et al., Am. Fam. Phys., 143 (1988)-   Scrima et al., Sleep, 13(6) 479 (1990)-   Series et al., Am. Rev. Respir. Dis., 145(6) 1378 (1992)-   Scharf et al., J. Clin Psychiatry, 46(6) 222 (1985)-   Snead and Morley, Brain Res., 227(4) 579 (1981)-   Stock et al., Naunyn Schmiedebergs Arch Pharmacol., 278(4) 347    (1973)-   Strong, Lancet, 1(8389) 1304 (1984)-   Yamada et al., Electroencephalogr. Clin. Neurophysiol., 22(6) 558    (1967)

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A compound of the formula (II):(R′O(CH₂)₃CO₂)_(m)(ROC(O)(CH₂)₃OC(O))_(q)—(X)—(Y)_(n)-(Z)_(n)-(CO₂(CH₂)₃CO₂R)_(p)(O₂C(CH₂)₃OR′)_(k)  (II)wherein R′ is H or a hydroxyl-protecting group, R is H, (C₁-C₄)alkyl orbenzyl, X and Z are each residues of a hydroxy group-containing aminoacid or a bis(carboxy)amino acid, Y is a moiety covalently linking X andZ, n is 0-1, m and k are 0 to the number of available hydroxy groups onthe amino acids X and Z; q and p are 0 to the number of available CO₂groups on amino acids X and Z, with the proviso that both m and q andboth p and k are not zero, or a pharmaceutically acceptable saltthereof.
 2. A compound of the formula (III):

wherein R¹ is H or a hydroxyl-protecting group, R is H, (C₁-C₄)alkyl orbenzyl, X is a residue of a hydroxy group-containing amino acids, Z isthe residue of a hydroxy group-containing amino acid or a bis(carboxy)group-containing amino acid, Y is a moiety covalently linking X and Z, nis 0-1, m is 1 to the number of available hydroxy groups in amino acidX, p is 1 to the number of available CO₂ groups on the amino acid X orZ, or a pharmaceutically acceptable salt thereof.
 3. The compound ofclaim 1 wherein each of m, q, p and k is
 1. 4. The compound of claim 1wherein m and k are 0, and q and p are
 1. 5. The compound of claim 1wherein n=0, m=0 and k=0 and X is glutamic acid, aspartic acid ortyrosine.
 6. The compound of claim 2 wherein m=p=1, n is 0 and X istyrosine, threonine, or serine.
 7. The compound of claim 2 whereinm=n=p=1 and Y is C(O)CH₂CH₂C(O) or C(O)CH═CH(CO).
 8. A compound offormula (IV):

wherein L and L′ are individually H, (C₁-C₆)alkyl or a hydroxylprotecting group or an organic moiety comprising at least one fattyalcohol, fatty ester or analog thereof, wherein at least one of L and L′is said moiety.
 9. The compound of claim 8 wherein at least one of L′ orL is -(A)(Y)(Z)_(n), wherein A is (C₁-C₆)alkyl, Y is H, OH N(R¹)(R²)(R³)or [—O(PO₃ ⁻)-AN(R¹)(R²)(R³), wherein R¹, R² and R³ are each(C₁-C₄)alkyl or R¹ and R² together with N are a (C₅-C₇)heterocyclicring, optionally substituted with 1 or 2 N(R³), S, non-peroxide O or acombination thereof, n is 1-2 and Z is YR, wherein Y is O, S, NH,N(CH₃), NHC(O) or OC(O) and R is (C₈-C₂₂)alkyl, optionally substitutedwith 1-2 double bonds, or a pharmaceutically acceptable salt thereof,with the proviso that when one of L or L′ is1,3-dihexadecanoylprop-2-yl, the other is not H.
 10. The compound ofclaim 9 wherein L′ is -(A)(Y)(Z)_(n) and L is H, (C₁-C₆)alkyl or ahydroxyl protecting group.
 11. The compound of claim 9 or 10 wherein Yis OC(O).
 12. The compound of claim 8 wherein R is (C₁₀-C₂₂)alkyl. 13.The compound of claim 9 or 10 wherein Y is —O(PO₃ ⁻)CH₂CH₂N(CH₃)₃ ⁺. 14.The compound of claim 9 or 10 wherein (A)(Y)(Z)_(n) is —CH[CH₂Y][CH₂Z].15. A method for treating a mammal afflicted with a condition orpathology amenable to treatment by gamma-hydroxy butyrate (GHB)comprising administering to said mammal an effective amount of acompound of formula (II):(R′O(CH₂)₃CO₂)_(m)(ROC(O)(CH₂)₃OC(O))_(q)—(X)—(Y)_(n)-(Z)_(n)-(CO₂(CH₂)₃CO₂R)_(p)(O₂C(CH₂)₃OR′)_(k)  (II)wherein R′ is H or a hydroxyl-protecting group, R is H, (C₁-C₄)alkyl orbenzyl, X and Z are each residues of a hydroxy group-containing aminoacid or a bis(carboxy)amino acid, Y is a moiety covalently linking X andZ, n is 0-1, m and k are 0 to the number of available hydroxy groups onthe amino acids X and Z; q and p are 0 to the number of available CO₂groups on amino acids X and Z, with the proviso that both m and q andboth p and k are not zero, or a pharmaceutically acceptable saltthereof.
 16. A method for treating a mammal afflicted with a conditionor pathology amenable to treatment by gamma-hydroxy butyrate (GHB)comprising administering to said mammal an effective amount of acompound of formula (III):

wherein R¹ is H or a hydroxyl-protecting group, R is H, (C₁-C₄)alkyl orbenzyl, X is a residue of a hydroxy group-containing amino acids, Z isthe residue of a hydroxy group-containing amino acid or a bis(carboxy)group-containing amino acid, Y is a moiety covalently linking X and Z, nis 0-1, m is 1 to the number of available hydroxy groups in amino acidX, p is 1 to the number of available CO₂ groups on the amino acid X orZ, or a pharmaceutically acceptable salt thereof.
 17. A method fortreating a mammal afflicted with a condition or pathology amenable totreatment by gamma-hydroxy butyrate (GHB) comprising administering tosaid mammal an effective amount of a compound of formula (IV):

wherein L and L′ are individually H, (C₁-C₆)alkyl or a hydroxylprotecting group or an organic moiety comprising at least one fattyalcohol, fatty ester or analog thereof, wherein at least one of L and L′is said moiety.